Bioinformatory‐assisted analysis of next‐generation sequencing data for precision medicine in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence‐based software that analyzes next‐generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS,TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence‐based software, could be conducted within a 2‐week period, thus being feasible for clinical routine. Therapy recommendations were principally off‐label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome‐associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software‐analysis of NGS data provides evidence‐based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC.

Metabolomics technology and bioinformatics for precision medicine

“…Perhaps, because of the promise this new technology holds in the early detection of cancer, significant efforts have gone into deciphering genomic alternations or other biomarkers in different types of cancer, such as mRNA/miRNA, cytokine or urine-based metabolites in lung cancer [195], or novel mutations, fusions or copy number variations in biliary tract cancer [284]. A recently developed evidence-based software TREATMENTMAP used a panel of pharmacogenomic markers to probe the genomic sequences from pancreatic tumors; this diagnostic tool was shown to identify known driver mutations as well as biomarkers for effective treatment [285].…”

Personalisierte Krebsmedizin im klinischen Alltag – Reflektion und Perspektive

“…Die Tumorsequenzierung mittels NGS ("whole exome sequencing") wurde von einem kommerziellen, TÜV/ISO-zertifizierten Labor durchgeführt. Die Analyse der Sequenzdaten erfolgte mit einer ebenfalls kommerziellen, CE-zertifizierten Software (MH Guide™) [12]. Diese Software produziert evidenzbasierte Empfehlungen basierend auf dem gesamten Biomarkerprofil (d. h. der Gesamtheit aller gefundenen Mutationen), resultierend in Empfehlungen für Medikamente, gone through multiple lines of treatment and could not be cured any more.…”

Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy

“…Owing to the position and composition of pancreaticobiliary tumours, tissue samples are frequently acellular, making diagnostics challenging. Recently, the utility of next-generation sequencing was explored as a technique that allows the detection of low-abundance mutations and abnormalities in small amounts of material 40 . Changes in the metabalome are also being explored as a potential diagnostic tool in pancreaticobiliary malignancy 41 .…”